High-Dose Combination Chemotherapy Plus Peripheral Stem Cell Transplantation Compared With Standard Combination Chemotherapy in Treating Women With High-Risk Breast Cancer

NCT00002784 | Completed Phase 3 DMC

• 3 other identifiers: CDR0000064834IBCSG-15-95EU-96021
• Study Type: interventional
• Target: 344
• Locations: 2 countries
• Sites: 11

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. It is not yet known if high-dose combination chemotherapy plus peripheral stem cell transplantation is more effective than standard combination chemotherapy for breast cancer. PURPOSE: Randomized phase III trial to compare high-dose combination chemotherapy plus peripheral stem cell transplantation with standard combination chemotherapy in treating women with stage II or stage III breast cancer.

Conditions

Breast Cancer

Keywords

stage II breast cancer; stage IIIA breast cancer

Outcome Measures

Primary Outcomes (1)

• Disease-free survival.

  Time from randomization to recurrence (including recurrence isolated to the breast), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first.

  16 years after randomization.

Secondary Outcomes (3)

• Overall survival.

  16 years after randomization.

• Toxicity.

  5 years after randomization.

• Quality of life.

  16 years after randomization.

Study Arms (2)

Standard chemotherapy

ACTIVE COMPARATOR

EC/AC x 4 followed by CMF x 3 and tamoxifen to 5 years after randomization.

Drug: CMF regimen; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: epirubicin hydrochloride; Drug: fluorouracil; Drug: methotrexate; Drug: tamoxifen citrate; Radiation: low-LET electron therapy; Radiation: low-LET photon therapy

Dose-intensive EC

EXPERIMENTAL

High-dose EC x 3 supported by peripheral blood progenitor cells and tamoxifen to 5 years after randomization.

Biological: filgrastim; Drug: cyclophosphamide; Drug: mesna; Drug: tamoxifen citrate; Procedure: peripheral blood stem cell transplantation; Radiation: low-LET electron therapy; Radiation: low-LET photon therapy

Interventions

filgrastim BIOLOGICAL

Filgrastim 10 mg/kg/d sc for 6 days after randomization.

Dose-intensive EC

CMF regimen DRUG

Cyclophosphamide 100 mg/m2 orally days 1 - 14, methotrexate 40 mg/m2 iv days 1 and 8, 5-fluorouracil 600 mg/m2 iv days 1 and 8. Repeat every 28 days.

Standard chemotherapy

cyclophosphamide DRUG

For high-dose EC arm: cyclophosphamide 4 gm/m2 iv as 4 divided doses. For standard chemotherapy arm: cyclophosphamide 600 mg/m2 iv day 1 of 21-day EC cycles, and cyclophosphamide 100 mg/m2 orally on days 1-14 of 28-day CMF cycles.

Dose-intensive EC; Standard chemotherapy

doxorubicin hydrochloride DRUG

Doxorubicin 60 mg/m2 iv on day 1 of 21-day cycles of AC.

Standard chemotherapy

epirubicin hydrochloride DRUG

Epirubicin 90 mg/m2 iv on day 1 of 21-day cycles of EC.

Standard chemotherapy

fluorouracil DRUG

5-fluorouracil 600 mg/m2 iv days 1 and 8 of 28-day cycles of CMF.

Standard chemotherapy

mesna DRUG

MESNA (7.2 gm/m2) on days 2 and 3 of 21-day cycles of dose-intensive EC.

Dose-intensive EC

methotrexate DRUG

Methotrexate 40 mg/m2 iv on days 1 and 8 of 28-day cycles of CMF.

Standard chemotherapy

tamoxifen citrate DRUG

Tamoxifen 20mg daily for 5 years or until relapse.

Dose-intensive EC; Standard chemotherapy

peripheral blood stem cell transplantation PROCEDURE

Peripheral blood progenitor cells (PBPC) infusion on day 5 of each 21-day cycle of dose-intensive EC.

Dose-intensive EC

low-LET electron therapy RADIATION

Radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Dose-intensive EC; Standard chemotherapy

low-LET photon therapy RADIATION

radiation therapy to the conserved breast is mandatory, to be carried out according to the prospectively defined guidelines of each participating institution; either after all chemotherapy or integrated into CMF as agreed per institution. Radiotherapy to the chest wall following mastectomy is optional according to the prospectively defined guidelines of each participating institution.

Dose-intensive EC; Standard chemotherapy

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: Histologically proven breast carcinoma in one of the following categories: 10 or more involved axillary nodes 5 or more involved axillary nodes and either: Primary tumor estrogen receptor (ER)-negative (less than 10 femtomoles per milligram of cytosol protein) T3 tumor (regardless of ER status) Total mastectomy or breast-conserving procedure (lumpectomy or quadrantectomy) required within 6 weeks prior to randomization Tumor confined to breast and axillary nodes (T1a-c, T2, or T3, N1-2, M0 by the UICC staging system) The following conditions exclude entry: Satellite skin nodules distant from the primary tumor Supraclavicular node involvement Inoperable, matted axillary nodes Fixation of primary tumor to chest wall (excluding pectoralis major) Bilateral breast cancer (any mass in opposite breast unless biopsy-proven benign) Hot spots on bone scintigram (unless confirmed to be benign) Skeletal pain of unknown cause Hormone receptor status: ER status determination preferred, but not required PATIENT CHARACTERISTICS: Age: 16-65 Sex: Women only Menopausal status: Any status Performance status: ECOG 0-2 Hematopoietic: WBC at least 4,000 Platelets at least 100,000 Hepatic: Bilirubin no greater than 1.1 mg/dL (20 micromoles/L) AST no greater than twice normal Renal: Creatinine no greater than 1.3 mg/dL (120 micromoles/L) Cardiovascular: Left ventricular ejection fraction greater than 50% by MUGA Other: No second malignancy except: Basal cell carcinoma Adequately treated carcinoma in situ of the cervix No significant nonmalignant disease that would preclude participation No psychiatric or addictive disorder that would compromise informed consent or participation No pregnant or nursing women Adequate contraception strongly advised for fertile women PRIOR CONCURRENT THERAPY: No prior therapy for breast cancer other than surgery (see Disease Characteristics)

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead

Study Sites (11)

Newcastle Mater Misericordiae Hospital

Newcastle, New South Wales, NSW 2310, Australia

Location

Royal Prince Alfred Hospital, Sydney

Sydney, New South Wales, 2050, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Queen Elizabeth Hospital

Adelaide, South Australia, 5011, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Swiss Institute for Applied Cancer Research

Bern, CH-3008, Switzerland

Location

Inselspital, Bern

Bern, CH-3010, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, CH-1011, Switzerland

Location

Istituto Oncologico della Svizzera Italiana

Lugano, CH-6900, Switzerland

Location

Kantonsspital - Saint Gallen

Sankt Gallen, CH-9007, Switzerland

Location

Universitaetsspital

Zurich, CH-8091, Switzerland

Location

Related Publications (7)

• Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, Holmberg SB, Lindtner J, Snyder R, Thurlimann B, Murray E, Viale G, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008 Jun 20;26(18):3006-14. doi: 10.1200/JCO.2007.14.9336. Epub 2008 May 5.

  PMID: 18458044 BACKGROUND

• Keshaviah A, Dellapasqua S, Rotmensz N, Lindtner J, Crivellari D, Collins J, Colleoni M, Thurlimann B, Mendiola C, Aebi S, Price KN, Pagani O, Simoncini E, Castiglione Gertsch M, Gelber RD, Coates AS, Goldhirsch A. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. Ann Oncol. 2007 Apr;18(4):701-8. doi: 10.1093/annonc/mdl492. Epub 2007 Jan 20.

  PMID: 17237474 BACKGROUND

• Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. doi: 10.1093/annonc/mdp024. Epub 2009 May 25.

  PMID: 19468030 RESULT

• International Breast Cancer Study Group; Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. doi: 10.1200/JCO.2005.03.5196.

  PMID: 16421418 RESULT

• Basser RL, Abraham R, To LB, Fox RM, Green MD. Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer. Ann Oncol. 1999 Jan;10(1):53-8. doi: 10.1023/a:1008390203340.

  PMID: 10076722 RESULT

• Basser RL, To LB, Collins JP, Begley CG, Keefe D, Cebon J, Bashford J, Durrant S, Szer J, Kotasek D, Juttner CA, Russell I, Maher DW, Olver I, Sheridan WP, Fox RM, Green MD. Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up. J Clin Oncol. 1999 Jan;17(1):82-92. doi: 10.1200/JCO.1999.17.1.82.

  PMID: 10458221 RESULT

• Basser RL, To LB, Begley CG, Juttner CA, Maher DW, Szer J, Cebon J, Collins JP, Russell I, Olver I, et al. Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells. Clin Cancer Res. 1995 Jul;1(7):715-21.

  PMID: 9816037 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Filgrastim; CMF regimen; Cyclophosphamide; Doxorubicin; Epirubicin; Fluorouracil; Mesna; Methotrexate; Tamoxifen; Peripheral Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Russell Basser, MD

  Melbourne Health

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 1999
• First Posted: July 29, 2004
• Study Start: June 1, 1996
• Primary Completion: August 1, 2011
• Study Completion: December 1, 2011
• Last Updated: April 4, 2013

Record last verified: 2012-07

Locations

CH (6); AU (5)